Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

Oncogene volume 25, pages 7059–7069 (2006)Cite this article

Abstract

Skeletrophin (mindbomb homolog 2 (MIB2)) is a RING (Really Interesting New Gene) finger-dependent ubiquitin ligase, which targets the intracellular region of Notch ligands. A previous immunohistochemical study demonstrated that skeletrophin was downregulated in many melanomas. In the present study, we have identified a promoter region of skeletrophin on a CpG island and detected aberrant methylation of this region in six of 31 invasive melanomas, but in none of 25 benign nevi or five non-invasive superficial spreading melanomas. Subsequently, we found that a zinc-finger transcriptional factor Snail, which is overexpressed in many melanoma cells, repressed the skeletrophin promoter activity via an E-box-related element and was involved in downregulation of skeletrophin. An activator protein-2, which has a tumor suppressor-like role in melanoma, increased skeletrophin expression. Interestingly, exogenously expressed skeletrophin reduced melanoma cell invasion in vitro and in vivo. Colony formation in soft agar was also reduced in a RING motif-dependent manner, without affecting cell growth. We also found that skeletrophin downregulated transcription of the Met oncogene, which encodes the hepatocyte growth factor receptor and plays a role in the determination of the invasive phenotype of many malignant tumors. Finally, exogenously expressed skeletrophin, but not its RING mutant, increased transcription of Hes1 gene, a downstream effector of Notch pathway in melanoma cells. The present findings indicate that skeletrophin might be a novel suppressor factor for melanoma invasion.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Bale SJ, Dracopoli NC, Tucker MA, Clark Jr WH, Fraser MC, Stanger BZ et al. (1989). N Engl J Med 320: 1367–1372.

  • Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I et al. (2005). J Clin Invest 115: 3166–3176.

  • Dracopoli NC, Harnett P, Bale SJ, Stanger BZ, Tucker MA, Housman DE et al. (1998). Proc Natl Acad Sci USA 86: 4614–4618.

  • Fan X, Inda MM, Tunon T, Castresana JS . (2002). Oncol Rep 9: 181–183.

  • Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D et al. (2004). Cancer Res 64: 7787–7793.

  • Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S et al. (2005). Cancer Res 65: 9328–9337.

  • Goldstein AM, Nicholas CD, Ho EC, Fraser MC, Kearns KS, Bale SJ et al. (1993). Am J Hum Genet 52: 537–550.

  • Grichnik JM, Burch JA, Schulteis RD, Shan S, Liu J, Darrow TL et al. (2006). J Invest Dermatol 126: 142–153.

  • Herman JG, Graf JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Proc Natl Acad Sci USA 93: 9821–9826.

  • Hewett PW, Daft EL, Murray JC . (1998). Biochem Biophys Res Commun 252: 546–551.

  • Hoek K, Rimm DL, Williams KR, Zhao H, Ariyan S, Lin A et al. (2004). Cancer Res 64: 5270–5282.

  • Ishihara T, Takeuchi T, Nishimori I, Adachi Y, Minakuchi T, Fujita J et al. Virchow Archiv, in press.

  • Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D et al. (2003). Dev Cell 4: 67–82.

  • Jin Y, Blue EK, Dixon S, Shao Z, Gallagher PJ . (2002). J Biol Chem 277: 46980–46986.

  • Koo BK, Lim HS, Song R, Yoon MJ, Yoon KJ, Moon JS et al. (2005a). Development 132: 3459–3470.

  • Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH et al. (2005b). J Biol Chem 280: 22335–22342.

  • Leong KG, Karsan A . (2006). Blood 107: 2223–2233.

  • Mauhin V, Lutz Y, Dennefeld C, Alberga A . (1993). Nucleic Acids Res 21: 3951–3957.

  • Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R et al. (1993). Br J Cancer 68: 746–750.

  • Nickoloff BJ, Osborne BA, Miele L . (2003). Oncogene 22: 6598–6608.

  • Nijjar SS, Wallace L, Crosby HA, Hubscher SG, Strain AJ . (2002). Am J Pathol 160: 1695–1703.

  • Parr C, Watkins G, Jiang WG . (2004). Int J Mol Med 14: 779–786.

  • Pitsouli C, Delidakis C . (2005). Development 132: 4041–4050.

  • Poetsch M, Dittberner T, Woenckhaus C . (2003). Melanoma Res 13: 29–33.

  • Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK . (2001). J Biol Chem 276: 24661–24666.

  • Radtke F, Raj K . (2003). Nat Rev Cancer 3: 756–767.

  • Stella MC, Trusolino L, Pennacchietti S, Comoglio PM . (2005). Mol Cell Biol 25: 3982–3996.

  • Takeuchi T, Adachi Y, Ohtsuki Y . (2005). Am J Pathol 166: 1817–1826.

  • Takeuchi T, Heng HHQ, Ye CJ, Liang SB, Sonobe H, Ohtsuki Y . (2003). Am J Pathol 163: 1395–1404.

  • Takeuchi T, Kuro-o M, Miyazawa H, Ohtsuki Y, Yamamoto H . (1997). J Immunol 159: 726–733.

  • Takeuchi T, Liang SB, Matsuyoshi N, Zhou S, Miyachi Y, Sonobe H et al. (2002). Lab Invest 82: 1023–1029.

  • Takeuchi T, Misaki A, Liang SB, Tachibana A, Hayashi N, Sonobe H et al. (2000). J Neurochem 74: 1489–1497.

  • Tellez C, Bar-Eli M . (2003). Oncogene 22: 3130–3137.

  • Wang W, Struhl G . (2005). Development 132: 2883–2894.

  • Zweidler-McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC et al. (2005). Blood 106: 3898–3906.

Download references

Acknowledgements

We are grateful to Drs Karen Artzt (The University of Texas at Austin), Ajay Chitnis (National Institutes of Health, USA) and YY Kong (Pohang University of Science and Technology, South Korea) for helpful suggestions and encouragements. We thank Mr Yamaguchi Takuya, Miss Nakamura Naoyo (Department of Pathology, Kochi Medical School, Japan) and Miss Matumura, Rumi (Division of Molecular Biology, Kochi Medical School, Japan) for providing their skillful techniques. We also thank Miss Minakuchi, Tomoko (Department of Gastroenterology and Hepatology, Kochi Medical School) for kind assistance with the quantitative RT–PCR. This study was supported by grants from the Ministry of Education of Japan (12670165, 13670177 and 17590270), the Medical Research Fund of Kochi Medical School and a Project Grant for short study abroad from the Vice-Chancellor of Kochi Medical School.

Author information

Authors and Affiliations

  1. Department of Pathology, Kochi Medical School, Kochi, Japan

    T Takeuchi, Y Adachi, M Furihata & Y Ohtsuki

  2. Department of Laboratory Medicine and Pathology, National Hospital Organization Fukuyama Medical Center, Hiroshima, Japan

    H Sonobe

Authors
  1. T Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Sonobe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Furihata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Ohtsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Takeuchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takeuchi, T., Adachi, Y., Sonobe, H. et al. A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion. Oncogene 25, 7059–7069 (2006). https://doi.org/10.1038/sj.onc.1209688

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209688

Keywords

This article is cited by

Search

Advanced search

Quick links